The present invention relates to an apparatus and method for the local delivery of drugs.
Local delivery of drugs has been previously accomplished by conjugating a drug to biocompatible or biodegradable macromolecules, e.g. biopolymers, lipids, polysaccharides, proteins including albumin and immunoglobulines, which have a particular receptor specificity. In this way the drug can be transferred to a particular part of the human body which is subject to treatment with the particular drug. For example, Oppenheim. et al. disclose in U.S. Pat. No. 4,107,288 a process for the preparation of drug containing gelatine particles having a diameter mainly below 500 xcexcm which can be administered parenterally.
Solid serum albumin spherules having 5 to 30% by weight of an entrapped drug are disclosed by Yapel, Jr. in U.S. Pat. No. 4,147,767. The spherules are particularly suited for intravenous injection into the human body whereafter the drug is released from the spherule in a biphasic manner having an initial fast-release phase followed by a slow release phase.
A method of preparing aqueous suspensions of drug containing spherules comprising a phospholipid has been described by Suzuki, et al. in U.S. Pat. No. 4,016,100. These spherules, which are suitable for injection as well as oral administration, give controlled release of the entrapped drug after administration.
Although the particles and spherules described above can be used to deliver a drug to a particular part of the body, e.g. the lungs or the liver, a local and site specific actively controlled release of the drug contained by said particles and spherules has not be achieved in the prior art. Actively controlled release refers to the ability to spatially localize, modulate, and monitor the delivery of drugs for optimal benefit. In a mammal, i.e. a human or animal, the release of the drug contained by said particles and spherules is determined by the biological processes and functions of the mammalian body, i.e. the biodegradation of the particles, and can not be influenced actively and/or in a site specific manner.
It is therefore not unlikely that while being transferred to the desired area in the mammalian body by the blood circulation, these drug containing particles and spherules described in the prior art may be partly inactivated or even disintegrated. Obviously this will give rise to serious consequences for the patient, especially when drugs are used which are highly toxic to the mammalian body. Consequently, the efficacy of the methods described above for treating a certain disorder can be considered to be rather low.
In addition, the prior art does not provide a method for monitoring the release of a drug from particles and spherules neither in space nor in time. Hence, the effective concentration of the drug in the desired area of the mammalian body can therefore not be determined.
The present invention relates to particles and spherules which interact with energy in-situ to modulate the release of drugs and also allow detection of the particles and spherules from the energy interactions. Biocompatible or biodegradable macromolecules labelled with solid gold particles, e.g. gold-albumin, have found application as cytochemical markers in electron microscopy. Solid gold particles bind the macromolecule irreversibly whereby the macromolecule generally preserves its specific biological activity. Because of their high electron density, these gold particles can be observed by electron microscopy enabling the detection of intercellular locations of the macromolecule. Such systems have been described by Horisberger, et al., Histochem. 80, 1984, 13-18, and by Slot, et al., Eur. J. Cell Biol. 38, 1985, 87-93. However, neither Horisberger, et al. nor Slot, et al. describe or suggest that these gold-albumin particles can be used as local drug delivery systems.
Particles prepared from biocompatible or biodegradable materials, which can be detected by ultrasonic imaging are known as well. These particles comprise so-called microparticles, microbubbles, microspheres or microcapsules containing gaseous components capable of reflecting ultrasonic waves. WO-9.112.823 discloses a process for preparing such particles comprising the formation of water-dispersable, preferably proteinaceous, microcapsules having a liquid or solid core by conjugation of oil/water bubbles with biocompatible or biodegradable materials, e.g. albumin, followed by the removal of at least some of said liquid or solid to create a microcapsule containing a gas. The microcapsules are preferably 0.1 to 500 xcexcm in diameter. In WO-9.112.823 it is neither described nor suggested that such particles can be used for the active and controlled delivery of a drug to a specific area of the mammalian body.
The problems which are encountered when the above described systems are used for the local delivery of a drug can be summarized as follows: 1) the release of the entrapped drug from the local drug delivery system can not be controlled actively and/or in a site specific manner, 2) before the systems reach the area in the mammalian body to be treated they might be inactivated or even disintegrated, and 3) the release and/or the effective concentration of the drug in the area to be treated can not be determined.
The present invention is directed to a local and site-specific drug delivery system for delivering a drug to a specific site. The drug delivery system is characterized by the combination of a carrier material which reflects or absorbs or emits electromagnetic or mechanical (e.g. ultrasonic) vibrations enabling the monitoring of the material, a drug associated with the carrier material, and local-delivery means for delivering the carrier material and the drug to a specific site.
The local-delivery means may comprise a local-delivery catheter, such as a balloon-type catheter, and the drug delivery system may additionally include means for monitoring the delivery of the drug to the specific site, such as an ultrasonic imaging system. The drug delivery system may also include means for inducing release of the drug from the carrier material when the carrier material is at the specific site, such as means for generating electromagnetic or mechanical vibrations.
The carrier material may comprise an ultrasonic contrast agent in the form of microparticles, microbubbles, microspheres or microcapsules. The carrier material may comprise microbubbles having a diameter of between 1-1000 xcexcm, between 1-100 xcexcm, or between 1-20 xcexcm.
Alternatively, the local-delivery means may comprise a targeting agent associated with the carrier material, the targeting agent capable of binding to the specific site within the individual. The targeting agent may be a protein or an antibody, such as a glycoprotein IIa/IIB receptor antibody, Von Willebrand""s factor antibody, an antitumor antibody, hepatic cellular antibody, a white blood cell antibody, or antifibrin antibody.
The carrier material may be in the form of an ultrasonic contrast agent, such as gas microbubbles having a gas and a shell, wherein the drug is embedded in the microbubble shell, encapsulated in the microbubble, or bound to a surface of the microbubble shell. The targeting agent may be bound to a surface of the microbubble shell.
The drug, which may comprise a chemotherapy agent, a thrombolytic drug, an anti-infection agent, vasodilation agent, tissue protective agent, or a gene therapy agent, may be selected from the group consisting of acebutolol, acetylsalicylic acid, adenosine, ATP, alfentanil, alprazolam, azlocillin, betamethasone, bleomycin, captopril, carbenicillin, cefamandole, cefazolin, cefonicid, ceforanide, cefotaxime, cefoxitin, clonidine, cloxacillin, cyclophosphamide, cytarabine, dexamethasone, dicloxacillin, diazepam, diazoxide, digitoxin, digoxin, diltiazem, diphenihydramine, disopyramide, doxorubicin, doxycycline, ceftazidime, ceftizoxime, cefuroxime, cephalexin, cephalothin, cephapirin, chloramphenicol, chloroquine, chlorothiazide, chlorpropormide, chlorthalidone, cimetidine, clofibrate, ibuprofen, imipramine, indomethacin, isosorbide dinitrate, ketoprofen, labetalol, lidocaine, lorazepam, lorcainide, meperidine, mercaptopurine, methadone, methicillin, erythromycin, ethambutol, fentanyl, flucytosine, flunitrazepam, fluorouracil, flurazepam, furosemide, gold sodium thiomalate, haloperidol, heparin, hexobarbital, hydrochlorothiazide, nortriptyline, oxacillin, oxazepam, phenobarbital, phenylbutazone, phenytoin, pindolol, prazosin, prednisolone, prednisone, protenecid, procainamide, propranolol, methothexate, methyldopa, methylprednisolone, metoprolol, metronidazole, mexiletine, mezlocillin, minocycline, morphine, moxalactam, nadolol, nafcillin, naproxen, nifedipine, nitrazepam, theopental, ticarcillin, timolol, tocainide, tolbutamide, tolmetin, triamterene, triazolam, trimethoprim, tubocurarine, urokinase, valproic acid, verapamil, warfarin, protriptyline, pyrimethamine, quinidine, ranitidine, rifampin, salicylic acid, streptomycin, streptokinase, sulfadiazine, sulfamethoxazole, sulfisoxazole, ternazepam, terbutaline, tetracycline, theophylline, andtissue plasminogen activator (tpa).
The invention is also directed to a method of treating a specific site in a mammal with a drug. The method is characterized by the steps of: (a) providing a carrier material which reflects or absorbs or emits electromagnetic or mechanical vibrations enabling the monitoring of the material and a drug associated with the carrier material, and (b) delivering the carrier material and the drug to a specific site in a mammal.
The method may also include the step of generating an image of the carrier material at the specific site, such as by ultrasonically generating an image of the carrier material at the specific site, and/or the step of inducing the drug to be released from the carrier material when the carrier material and the drug are at the specific site. The method may further include the step of inducing the drug to be released from the carrier material when the carrier material and the drug are at the specific site by subjecting the carrier material to ultrasonic vibrations.
The invention is also directed to a method of delivering a drug to a specific target site in an individual having the steps of (a) administering an ultrasonic contrast agent-drug complex to an individual, wherein the complex comprises an ultrasonic contrast agent, a drug, and optionally, a targeting agent capable of binding the ultrasonic contrast agent to the target site in the individual, (b) monitoring the individual using ultrasound to determine an arrival of the complex at the target site in the individual, (c) releasing the drug at the target site by applying sufficient energy to rupture the complex at the target site, and (d) optionally, imaging the target site using ultrasound techniques to monitor release of the drug. The target site in a patient for many applications may be generalized areas of tissue or an organ of known anatomical location such as the heart or kidneys. The general area could be irradiated with sufficient energy for drug release without imaging the target site.
These and other features of the present invention will be apparent to those of ordinary skill in the art in view of the detailed description of the preferred embodiment, which is made with reference to the drawings, a brief description of which is provided below.